This proposal is designed to study the regulation of the voltage-gated potassium channel, Kv1.3, by insulin in the mitral cells of the olfactory bulb. Modulation of mitral cell activity alters olfactory sensory perception;therefore, understanding how Kv1.3 current is influenced by insulin via phosphatase activation will elucidate potential mechanisms that control mitral cell firing. The objective of this research is to understand how the regulation of the dephosphorylation of Kv1.3 could potentially lead to altered insulin signaling in the olfactory bulb, which results in changes in mitral cell firing and olfactory sensory perception. The specific aims of this proposal are to determine the role of a protein tyrosine phosphatase, SHP-2, in the insulin signaling cascade that regulates Kv1.3 activity in the olfactory bulb. Insulin stimulation in the presence and absence of SHP-2 will be utilized to elucidate the link between the phosphorylation state and the electrical activity of Kv1.3. Histological experiments will identify the localization of SHP-2 in the olfactory system. While both native olfactory tissue and parallel cell culture experiments will be used to measure phosphatase-induced dephosphorylation of Kv1.3, and co-immunoprecipitations will determine proteins that form complexes with the channel. Electrophysiological approaches will identify potential mechanisms regulating the outward current generated by Kv1.3 in immortalized cell lines and in mitral cells. Kv1.3 in mitral cells of the olfactory bulb has recently been linked to regulation of metabolism. Given that this channel is regulated by insulin and the insulin signaling cascade can be drastically altered during diabetes and obesity, it is important to understand all aspects of the regulation of Kv1.3 activity in both basal and insulin-stimulated conditions. SHP-2 has also been linked to the regulation of metabolic state and development of diabesity;therefore, it is crucial to understand how SHP-2 modulates Kv1.3 activity in response to insulin signaling in the olfactory bulb mitral cells in terms of both olfactory perception and metabolic regulation. PUBLIC HEALTH RELEVANCE: Kv1.3 is an ion channel that regulates the sense of smell. Both Kv1.3 and the phosphatase SHP-2 have been linked to regulating body weight, energy balance, and insulin levels. The link between these two proteins in the olfactory system has implications not only for sensory function but also for energy homeostasis.